Six people were taken to hospital suffering smoke inhalation, including Tompkins and her 10-year-old son, fathered by the rapper.
A passing off-duty police officer helped rescue the six people off an elevated deck in the home's back garden, fire officials said. All six were treated and released.
The blaze occurred days after an alleged confrontation inside the office of Tompkins' attorney about the home in Dix Hills, on Long Island near New York City.
The rapper does not live in the home and apparently wasn't there at the time of the fire.
Investigators from the Suffolk County arson squad were called to the scene after Dix Hills fire chief, Larry Feld, believed the fire may have been started deliberately "because of the intensity of the fire".
Earlier this year, Tompkins filed a suit against 50 Cent, whose real name is Curtis Jackson, claiming he had promised her the $2.4m (£1.5m) house more than a decade ago, but that since their break-up he now wanted to evict her and their son.
The rapper has been nominated for 13 Grammy awards.
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